N-hydroxymethylamino compounds



Patented Feb. 25, liifi l 3,122,550 N-l-lYBl-EGXYMETHYLAMEJQ CMGUNDS.lean Hcusser, Zurich, Switzerland, assignor to Rommel, S.A., Zurich,Switzerland No iErawi-ng. @rlginal application Get. 27, 1953, Ser.

No. 769,567, new Patent No. $368,146, dated Dec. 11, 1962. Eivlded andthis application June 28, 1962, Ser. No. 217,534 Claims priority,application Switzerland st. 31, 1957 Claims. (Cl. 202.68}

The present invention relates to therapeutically useful compoundscontaining the N-hydroxymethylamino group and to derivatives thereof.

In one asp ct thereof, the invention relates to mono-N-hydroxymethyldiamine salts and, more especially tomono-N-hydroxyrnethyl-piperazine salts(mono-N-hydroxymethyldiethylenediamine salts).

. It has been found that by the reaction of formaldehyde on piperazine(hexahydropyrazine, tag. in the form of the hexahydrate) polymericN-methylene-diethylenediamine is formed and that upon treatment of thelatter with an acid, the corresponding acid addition salt is obtained,in accordance with the following reaction scheme:

HN NH 0 H2O C H2O Hg poly (N-mcthylenediethylenc-diarnine) UK H2O Poly-(N-rnethy!ene-dicthylcne-diamine) 1 Na 0 II C Hz-C Hz HN NCHZOH.HX

C Hz 0 H2 (HX acid) reaction with the formaldehyde or with aformaldehyde-yielding agent can be carried out in an aqueous suspensionor in an organic suspending agent or solvent, such for example asmethanol. The reaction medium (eg. solvent) can be removed uponcompletion of the reaction.

The mono-Nhydroxymethylamino compounds (salts) produced according to theforegoing reaction possess an outstanding action against Gram-positiveand Gramnegative bacteria, pathogenic fungi and viruses. Thus, they havea bacteriostatic as Well as a bactericidal action against staphylococciand Ps. pyoc anca, for example, and are also effectivebacteriostatically as Well as bactericidally against cg. thrust (Mom'liaalbicans) and Triclzoph ton pedz's (Kaufimann-Vlolf), as Well as againstmany other pathogenic microorganisms.

The aforesaid salts are thus useful therapeutic agents, especiallydisinfectants. it is not at all necessary that the saidmono-N-hydroxymethyl amino salts be used as such against the pathogenicmicroorganisms. It is in fact advantageous to emoloy the intermediatepolymeric stagepoly- (N-rnethylene-diethylene diamine shoWn in theforegoing reaction scheme. This polymeric intermediate stage can t1 enbe converted in situ, so to speak, into the active form by means ofsubsequently added acid or by means of acid resulting from themetabolism of the microorganism or which can be present as metabolicproduct in the mucous membrane. it has been found that these acids areeffective to react with the polymeric intermediate form at lowconcentrations and at moderate temperatures, such as eg. bodytemperature (e.g. 37 C).

A significant aspect of the invention is thus the possibility ofadvantageously using the aforesaid reaction principle to achieve aso-called depot effect. This is realized, as already essentiallyindicated, by gradually and continuously producing the effectivemonomeric substance from the polymeric intermediate stage at the situsof the desired antibacterial action, e.g. at a point on the mucousmembrane.

The properties of the aforesaid salts make possible a wide variation inthe form in which they are applied as d: infecting agents. These mayassume the form of salves, powder, tinctures, tablets, etc. These maycontain the salts or merely polymeric intermediates, to be convertedinto the efiec ive salts by means of acids. The acids may vary Widely,and may comprise inorganic acids such as hydrochloric acid, hydrobromicacid, boric acid, acetic acid, etc., as well as organic acids such asN-hyroxymethylsarcosine, citric acid, maleic acid, ethanesulfonic acid,etc, the sole condition being that the acid and the resultant salt bephysiologically tolerable.

further aspect of the invention resides in the fact that theN-hydroxymethylsarcosine which is useful as an acid in preparation of aneffective salt according to the present invention, as previouslyindicated, is itself an effective disinfecting agent againstGram-positive and Gram-negative bacteria, as Well as against pathogenicfungi and viruses, the a tivity being exhibited in its growth-inhibitingand killing action against such microorganisms. TheN-hydroxymethyl-sarcosine is thus capable of effecting a dual function,first as a salt-forming acid in the sense of the previous disclosure andsecondly as an effective disinfectant itself.

Advantage can be taken of the foregoing to de' elop a third andparticularly advantageous aspect of the invention, namely, theembodiment of forms of application which contain the two aforesaidchemotherapeutic agents. Such embodiments preferably take the form oflozenges or troclies cons .uted essentially by the aforementionedpoly-(N-methylene-diethylenediamine) i self or by the aforesaid salts orby a mixture of ingredients which can form such salts in situ; e.g.poly-(N-metnylene-diethylene-diamine) and l-lIlYClI'OXYIfiElhYlSdlCOSlllB.

Lozenges thus constituted-and containing, if desired, any otheringredient or ingredients usual in lozenges are especially useful forthe local treatment, prophylactically and/ or therapeutically, ofinfectious diseases of the oral and pharyngeal cavity.

it is noteworthy that such a lozenge provides a manifold source ofbactericidal and bacteriostatic activities, and that each of the sourcesconstituting the manifold source Works in a slightly different mannerfrom the other sources. Thus, the N-hydroxymethylsarcosine introducesimmediate disinfection by its initial and irnmediate action, while theeffect of the poly-(N-methylene-diethylene-diamine) sets in after ashort, biologically occasioned, starting period. The effective activityof the combination is, however, maintained for some length of time, sothat a depot-effect is obtained and a long-acting disinfection isrealized.

The active ingredients of the said lozenge are free of undesirable sideeffects.

The effectiveness of tie ll-hydroxymethylsarcosine against pathog ns isillustrated by the following results ascertained by thezone-ol-inhibition method:

1 o of zone in mm. +=destruction in the zone. =no destruction in thezone.

The effectiveness of the p ly-(N-methylene-diethylenediamine) againstpathogens is also readily demonstrated. Thus, saliva iniected withhaemolytic streptococci (155 organisms per milliliter of saliva) willcontain no more of these living Organisms after beng in contact with 2milligrams of poly-(N-methylene-d. thylene-diamine) per milliliter ofsaliva for minutes.

In the following exemplary embodiments of the invention, the parts areby weight unless otherwise indicated, and the relationship between partsby weight and parts by volume is the same as that between grams andmilliliters. Percentages are by weight; temperatures are in degreescentigrade.

Example 1 l9.4 parts of h xanydropyrazine hexahydrate (piperazine) aredissolved in 50 parts by volume of water. Thereupon, 7.9 parts by volumeof an aqueous formaldehyde solution of 38% strength is added slowly.Upon warming the reaction mixture sli htly, a voluminous whiteprecipitate forms, and this is separated by suction filtration, and thenwashed with water and dried.

9.8 parts by weight or" the so-obtained dry reaction product[poly-(N-methylene-diethylene-diamine)] are dissolved in 100 parts byvolume of normal aqueous hydrochloric acid, and the solution dried in avacuum desiccator at room temperature to 30). There are obtained 15parts by weight or" yellow-colored mono-N-hydroxymethyl-diethylenediarnine monohydrochloride, which melts atabout 175 with decomposition.

Example 2 19.4 parts of hexahydropyrazine hexahydrate are thoroughlyadmixed with 3.0 parts of paraformaldehyde. 100 parts by volume are thenadded to the solution, which is thereupon heated for 3 hours on theWaterbath. After cooling, the reaction product is separated by suctionfiltration, and then washed with water and dried.

918 parts of the so-obtained dry reaction product are dissolved in 106parts by volume of normal methanolic hydrochloric acid, after which themethyl alcohol is removed by cautious distillation under reducedpressure. The residue is mono--I-hydroxymetuyl-diefliylenediaminemonohydrochlori-de and melts at about 175 with decomposition.

Example 3 19.4 parts of hexahy ropyrazine hexahydrate are dissolved in50 parts by volume of Water. Thereupon, 7.9 parts by volume or" anaqueous formaldehyde solution of 38% strength is adde slowly. Uponwarming the reaction mixture slightly, a voluminous white precipitateforms, and this is separated by suction filtration, and then washed withwater and dried.

9.8 parts of he so-obtained dry reaction product are suspended water,and then 7.3 parts of adipic acid are added. After dissolution has beencompleted, the water is removed in a vacuum desiccator, leaving theformed mono N hydroxymethyl diet ylenediamine adipate as residue. Theproduct has a brown coloration and melts at about 232 withdecomposition.

4 Example 4 19.4 parts of hexahydropyrazine hexahydrate (piperazine) aredissolved in 50 parts by volume of water. Thereupon, 7.9 parts by volumeof an aqueous formaldehyde solution of 38% strength is added slowly.Upon warming the reaction mixture slightly, a voluminous whiteprecipitate forms, and this is separated by suction filtration, and thenwashed with water and dried.

The so-obtained polymeric condensation product is admixed, eg. withN-hydroxyrnethylsarcosine, and the mixture made up in per seconventional manneri.e. with usual additaments, e.g. sugar and thelike-into the form of lozenges or troches. Upon insertion of such alozenge or troche into the mouth, the action of the saliva converts themixture into the mono-N 1ydroxymethyl-piperazine-N-hydroxyrnethylsarcosine salt, which is active, bacteriostatically andbactericidally, against e.g. Streptococcus lzaem0lyt., type A14, B.diphlherz'ae, Staphylococcus lzaemolyt, Oxford strain, Pseudomoizaspyoc., etc. N-hydroxymethylsarcosine salt itself acts bacteriostaticallyand bactericidally as hercinbefore explained, and this applies also toany free poly-(N-rnethylene-diethylenediamine) present.

A preferred admixture in lozenge form contains about 2 parts ofN-hydroxymethylsarcosine per 10 parts of poly-(N-rnethylene-diethylene-diamine). Thus an illustrative composition maycontain Mg. Poly-(N-methylene diethylene-diamine) 10N-hydroxymethylsarcosine 2 Tetracaine hydrochloride 0.25

Other conventional lozenge-forming ingredients may also be present.Thus, among other things, menthol may be present to give a coolingeffect. The tetracaine hydrochloride may be omitted; its presence givesa rapid onset of analgesic influence which may be desirable in somecases.

Lozenges prepared according to this invention are usefulprophylactically for protection against droplet infections in crowdsduring flu periods, and during periods of high susceptibility torhinitis and colds. They are useful therapeutically against infectionsof the mouth and pharynx, tracheitis, gingivitis, oral thrush, etc.They, may also be used postoperatively, e.g. after a tonsillectomy orafter extraction of teeth. Useful doses are, for prophylactic purposes,3 to 4 lozenges daily; for therapeutic purposes 4 to 8 lozenges daily,as required. 7

Example 5 19.4 parts hexahydropyrazine hexahydrate (piperazine) aredissolved in 50 parts by volume of water. Thereupon, 7.9 parts by volumeof an aqueous formaldehyde solution of 38% strength is added slowly.Upon warming the reaction mixture slightly, a voluminous whiteprecipitate forms, and this is separated by suction filtration, and thenwashed with water and dried.

The so-obtained polymeric condensation product is admixed with boricacid, using equirnolar quantities, and the resulting mixtureincorporated into an ointment base which, per se, may be conventional.The polymer is cou- V verted into themono-N-hydroxymethyl-diethylerie-di amine-borate at the point ofapplication. This salt has excellent antibacterial properties e.g. inthe form of a.

1% ointment.

Example 6 and while keeping the temperature below 30. The resi due isthen maintained for 48 hours at 5 to 10, whereuponN-hydroxymethylsarcosine crystallizes out slowly. The crystals areseparated by suction filtration and then The 6 Washed with acetone.After drying, the yield of N- 2. Mono-N-hydroXyfiethyl-diethylenediaminen onohyhydroxymethylsarcosine is 55 parts. drochloride.

This application is a division of SeriaLNo. 769,567,Mono-N-hydroxymethyl-dlethylenedlamwe p 4. Mono-N-hydroxyrnethyl-diethylenediamine borate.

filed October 27, 1958, now Patent No. 3,068,146. I 1

Having thus disclosed the invention, What is claimed is: 5 Mono Nhydfoxymtllyl dlethyenediamme 1. An addition salt ofmono-N-hydroxymethyldiethylhydroxymathylsarcosme addition Saltenediamine with a physiologically acceptable acid. N f es it i

1. AN ADDITION SALT OF MONO-N-HYDROXYMETHYLDIETHYLENEDIAMINE WITH APHYSIOLOGICALLY ACCEPTABLE ACID.